title: Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity.
abstract: We have devised a procedure for the synthesis of analogs of combretastatin A-4 (CA-4) containing sulfur and selenium atoms as spacer groups between the aromatic rings. CA-4 is well known for its potent activity as an inhibitor of tubulin polymerization, and its prodrugs combretastatin A-4 phosphate (CA-4P) and combretastatin A-1 phosphate (CA-1P) are being investigated as antitumor agents that cause tumor vascular collapse in addition to their activity as cytotoxic compounds. Here we report the preparation of two sulfur analogs and one selenium analog of CA-4. All synthesized compounds, as well as several synthetic intermediates, were evaluated for inhibition of tubulin polymerization and for cytotoxic activity in human cancer cells. Compounds 3 and 4 were active at nM concentration against MCF-7 breast cancer cells. As inhibitors of tubulin polymerization, both 3 and 4 were more active than CA-4 itself. In addition, 4 was the most active of these agents against 786, HT-29 and PC-3 cancer cells. Molecular modeling binding studies are also reported for compounds 1, 3, 4 and CA-4 to tubulin within the colchicine site.
authors.affiliation: Universidade Federal de Mato Grosso do Sul, Instituto de Química, Laboratório LP4, Av. Filinto Müller, 1555, 79070-900 Campo Grande (MS), Brazil.
authors.forename: Edson dos A
authors.initials: Edos A
authors.lastname: dos Santos
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Ruoli
authors.initials: R
authors.lastname: Bai
authors.forename: James C
authors.initials: JC
authors.lastname: Burnett
authors.forename: Camila Santos Suniga
authors.initials: CS
authors.lastname: Tozatti
authors.forename: Danielle
authors.initials: D
authors.lastname: Bogo
authors.forename: Renata T
authors.initials: RT
authors.lastname: Perdomo
authors.forename: Alexandra M M
authors.initials: AM
authors.lastname: Antunes
authors.forename: M Matilde
authors.initials: MM
authors.lastname: Marques
authors.forename: Maria de F C
authors.initials: Mde F
authors.lastname: Matos
authors.forename: Dênis P
authors.initials: DP
authors.lastname: de Lima
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000633:toxicity; D001632:Bibenzyls / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D012643:Selenium / Q000737:chemistry* / Q000494:pharmacology; D013440:Sulfides / Q000737:chemistry* / Q000494:pharmacology; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001632:Bibenzyls; D013440:Sulfides; D050257:Tubulin Modulators; C040105:combretastatin; D012643:Selenium
keywords: Combretastatin A-4; Cytotoxicity; Diaryl selenide; Diaryl sulfide; Tubulin